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Death Receptor 3 (DR3) Gene Duplication in a Chromosome Region 1P36.3: Gene Duplication Is More Prevalent in Rheumatoid Arthritis

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Death Receptor 3 (DR3) Gene Duplication in a Chromosome Region 1P36.3: Gene Duplication Is More Prevalent in Rheumatoid Arthritis Genes and Immunity (2004) 5, 439–443 & 2004 Nature Publishing Group All rights reserved 1466-4879/04 $30.00 www.nature.com/gene FULL PAPER Death receptor 3 (DR3) gene duplication in a chromosome region 1p36.3: gene duplication is more prevalent in rheumatoid arthritis K Osawa1,2, N Takami1,2, K Shiozawa3, A Hashiramoto1,2,4 and S Shiozawa1,2,4,5 1Department of Rheumatology, Kobe University FHS School of Medicine, Kobe, Japan; 2Division of Bioregulation, Kobe University Graduate School of Medicine, Kobe, Japan; 3Department of Rheumatology, Konan Kakogawa Hospital, Kakogawa, Japan; 4Rheumatic Diseases Division, Kobe University Hospital, Kobe, Japan; 5Investigator of the Center of Excellence (COE), Japan The death receptor 3 (DR3) gene is a member of the apoptosis-inducing Fas gene family. In the current study, fluorescence in situ hybridization (FISH) and Fiber-FISH revealed the existence of a second DR3 gene B200 kb upstream of the original DR3 gene. The existence of the duplicated DR3 gene was confirmed by sequencing the corresponding human artificial chromosome clones as well as with quantitative PCR that measured the ratio of the DR3 gene mutation (Rm), intrinsic to rheumatoid arthritis (RA) patients, by simultaneous amplification of the normal and mutated DR3 sequences. The DR3 gene duplication measured by FISH was found to be more frequent in patients with RA as compared to healthy individuals. We therefore surmise that the human DR3 gene can be duplicated and that this gene duplication is more prevalent in patients with RA. Genes and Immunity (2004) 5, 439–443. doi:10.1038/sj.gene.6364097 Published online 8 July 2004 Keywords: gene duplication; death receptor 3 (DR3); fluorescence in situ hybridization (FISH); rheumatoid arthritis (RA) Introduction The current study examines the location of the DR3 gene based on the previous findings of Grenet et al,7 who The death receptor 3 (DR3), also named Ws1, Apo3, showed that the DR3 gene was duplicated and tandemly TRAMP, LARD, TR3 or TNFRSF25, is a member of the located in 1p36.2–1p36.3 in one male healthy donor. The tumor necrosis factor receptor (TNFR) superfamily authors suggested that duplicated genes are hemizy- which includes CD95/Fas, TNFR1, DR4, DR5 and gously deleted and/or possibly translocated to another DR6.1,2 DR3 contains four characteristic cysteine-rich chromosome as revealed in neuroblastoma cell lines. motifs as well as a death domain capable of inducing Using FISH, DNA sequencing and quantitative PCR, we cellular apoptosis and proliferation.3,4 We previously demonstrate here that the human DR3 gene can be assigned three principal chromosome regions of linkage, duplicated and that the duplicated DR3 gene is located D1S253/214, D8S556 and DXS1232, with maximum lod B200 kb upstream of the original DR3 gene sequence. scores (MLSs) 3.77/6.13, 4.20/1.14 and 2.35/3.03, respec- These findings are discussed in relation to the increased tively, by single/multi-point analyses.5 The death recep- frequency of gene duplication found in patients with RA. tor 3 (DR3) gene was mapped in the vicinity of D1S214/ 253 by the GeneBridge 4.0 radiation hybrid panel. Based on the EBI/Sanger Institute ENSEMBL database, D1S214 Results and discussion and D1S253 reside at 6.7 and 6.0 Mb, respectively, and Visual imaging DR3 at 6.2 Mb of chromosome 1p36. We subsequently To locate the DR3 gene using FISH, we used two probes, identified a polymorphism in the DR3 gene containing P1-derived artificial chromosome (PAC) clone 650H14 four single-nucleotide polymorphisms (SNPs) and one (GenBank accession no. AL158217) containing the DR3 locus of a 14 nucleotide deletion within exon 5 and intron gene and control PAC 126A5 (GenBank accession no. 5: g.1755A4G, g.2457_2470delT14, g.2531C4T, AL031447), each spanning the region between D1S214 g.2678A4T and g.2826A4G (GenBank accession nos. and D1S253 (Figure 1a). We found that the number of AB051850 to DR3 and AB051851 to mutant DR3). These fluorescent signals derived from PAC 650H14 was polymorphisms were found to be genetically associated between 2 and 4 (Figure 1b), whereas the number of with rheumatoid arthritis (RA).6 signals from PAC 126A5 was exactly 2, suggesting the existence of gene duplication in the chromosome region containing the DR3 gene. Correspondence: Dr S Shiozawa, Department of Rheumatology, Kobe We tried to confirm this by using the Fiber-FISH University FHS School of Medicine, 7-10-2 Tomogaoka, Sumaku, Kobe 654-0142, Japan. E-mail: [email protected] technique. The result showed that the PAC 650H14 Received 06 February 2004; revised 31 March 2004; accepted 31 (green) and PAC 126A5 (red) hybridization signals were March 2004; published online 8 July 2004 located in tandem. Interestingly, one additional green DR3 gene duplication and rheumatoid arthritis K Osawa et al 440 Figure 1 FISH and Fiber-FISH study. (a) Location of PAC 650H14 clone containing the DR3 gene and control PAC 126A5 clone. We performed FISH using PAC clone 650H14 (54 kb) and PAC 126A5 (112 kb). According to the NCBI and EBI/Sanger Institute ENSEMBL databases, PAC 650H14 contains the DR3 gene. Location of DR3 mutation was depicted in relation to transmembrane (TM) and death domain (DD) portions. a: g.1755A4G, b: g.2457_2470delT14, c: g.2531C4T, d: g.2678A4T and e: g.2826A4G (GenBank accession no. AB051850) corresponded to a: g.3658A4G, b: g.4360_4373delT14, c: g.4434C4T, d: g.4581A4T and e: g.4729A4G according to GenBank accession no. AY254324. Numbered boxes represented exons. cDNA nucleotide and amino acid numbered according to Marsters et al.4 (b) FISH imaging by using rhodamine-labeled PAC 650H14. Human peripheral blood mononuclear cells (PBMC), cultured with 10 mg/ml of phytohaemagglutinin (PHA) for 72 h, were treated with 40 ng/ml of colcemid for 15 min and a hypotonic 75 mM KCl solution at 371C for 20 min, followed by fixation in methanol-acetate (3:1). A drop of fixed cell suspension was placed on a glass slide at 721C and air-dried. DNA of PAC clones was labeled by nick translation with biotin-16-dUTP or digoxigenin-11-dUTP. The slides of metaphase chromosomes were denatured, dehydrated and air-dried. Denatured biotin- or digoxigenin-labeled DNA probes were then applied and hybridized signals were detected with avidin- FITC and biotinylated anti-avidin D for biotin-labeled probes or with Fab fragment of rhodamine-labeled anti-digoxigenin-fluorescein for digoxigenin-labeled probes. After counter-staining with 40,6-diamidino-2-phenylindole dihydrochloride (DAPI), more than 20 metaphase chromosomes were analyzed for the hybridization signals for each sample under Laser Scan Microscope LSM510 (Carl Zeiss GmbH, Stuttgalt, Germany). Four red dots indicated duplicated DR3 genes (arrows). (c) Fiber-FISH signal of PAC 126A5 (red) and PAC 650H14 (green) clones. For chromatin DNA fiber stream preparation (Fiber-FISH), glass slides containing a drop of fixed cell suspension were placed in phosphate- buffered saline, and a solution containing NaOH and ethanol was dragged over the cells using the short edge of a long coverslip. The slides were rinsed with methanol, air-dried and observed under LSM510.16,17 The position of duplicated gene revealed in relation to original PAC 650H14 and PAC 126A5 clones in a short chromosome 1p36.3 region prepared from a representative patient with RA. signal from PAC 650H14 was found in the upstream encompassing DR3 as TNFRSF12L to the NCBI database region of the DNA fiber towards the microsatellite without exactly locating its position. They simultaneously marker D1S214 (Figure 1c). As all signal lengths were reported in a separate manuscript, however, that the DR3 normalized according to the size of the probes gene as well as a duplicate copy of the gene were both (B0.01 mm/kb), the location of the duplicated region of located at 1p36 and separated by several megabases. PAC 650H14 was estimated to be B200 kb upstream of Second, Gururajan et al8 reported that the human Cdc2L1 the original PAC 650H14 towards the direction of the and Cdc2L2 genes, encoding almost identical protein centromere. This type of gene duplication was not kinases, were located at 1p36 in close proximity to p73 observed for PAC 126A5 or for the chromosomes and that the two genes were separated by only B50 kb. containing only one DR3 allele as revealed by FISH. Third, the two genes of the human Rhesus (RH) blood The DR3 gene duplication was not clearly assigned in the group locus, RHD and RHCE, also located in 1p36.1, are NCBI and the EBI/Sanger Institute ENSEMBL databases. separated by less than 200 kb.9 Therefore, we surmise that Gene duplication has been frequently reported in this the 1p36.2 and 1p36.3 regions, which contain a number of area of 1p36. First, Grenet et al7 registered a small region other members of the apoptotic gene family, including Genes and Immunity DR3 gene duplication and rheumatoid arthritis K Osawa et al 441 TNFRII,10 CD30,11 OX4012 and 4-1BB13,aresubjecttoa Figure 2b. In doing this, we found that, together, PAC similar phenomenon, and that gene duplication, if present, 650H14 and BAC 58A11 contained the entire DR3 gene is not unique to the DR3 gene. sequence. While both of these clones have not been previously reported to contain the DR3 gene, the NCBI Study of artificial clones database notes that the reported sequence did not Query of the NCBI database revealed the existence of include the entire insert sequences in the BAC 58A11 seven PAC and BAC clones of human chromosome 1 sequence. We may therefore assign the DR3 gene to PAC genomic contig that encompassed D1S214 and D1S253. 650H14.
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